tbuckley/cabot-search huggingface dataset:
PATH-06. Molecular subgrouping of medulloblastoma via low-depth whole genome bisulfite sequencing
Authors: Dean Thompson, Jemma Castle, Debbie Hicks, Ed Schwalbe, Steve Clifford
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: International consensus recognises four molecular subgroups of medulloblastoma, each with distinct molecular features and clinical outcomes. Assigning molecular subgroup is typically achieved via the Illumina DNA methylation microarray. Given the rapidly-expanding WGS capacity in healthcare institutions, there is an unmet need to develop platform-independent, sequence-based subgrouping assays. Whole genome bisulfite sequencing (WGBS) enables the assessment of genome-wide methylation status at single-base resolution. To date, its routine application for subgroup assignment has been limited, due to high economic cost and sample input requirements. Currently, no optimised pipeline exists that is tailored to handle samples sequenced at low-pass (i.e., &amp;lt;10x depth). METHODOLOGY: Two datasets were utilised; 36 newly sequenced low-depth (10x) and 42 publicly available high-depth (30x) WGBS medulloblastoma samples (n=34), alongside cerebellar control samples (n=8), all with matched DNA methylation microarray data. We applied imputation to low-pass WGBS data, assessed inter-platform correlation and identified molecular subgroups by directly integrating WGBS sample data with pre-existing array-trained models. We developed machine learning WGBS-based classifiers and compared performance against microarray. We optimised reference-free aneuploidy detection with low-pass WGBS and assessed concordance with microarray-derived aneuploidy calls. RESULTS: We optimised a pipeline for processing, QC, and analysis of low-pass WGBS data, suitable for routine molecular subgrouping and reference-free aneuploidy assessment that achieves 96% sensitivity compared to microarray approaches. A pilot study of the suitability of FFPE was promising, and we demonstrate that WGBS data can be integrated into existing array-trained models with high assignment probabilities. Also, WGBS-derived classifier performance measures exceeded microarray-derived classifiers. CONCLUSION: We describe a platform-independent WGBS assay for molecular subgrouping of medulloblastoma. It performs equivalently to array-based methods at increasingly comparable cost ($400 vs $580) and provides a proof-of-concept for routine clinical adoption using standard WGS technology. Finally, the full methylome enabled elucidation of additional biological heterogeneity that has hitherto been inaccessible.
LGG-37. Long-term Outcome, Visual Morbidity and Prognostic Factors in Infants and Young Children with Optic Pathway Glioma from the Great Ormond Street Hospital (GOSH) LGG - Cohort
Authors: Stefania Picariello, Brownen Walters, Richard Bowman, Olga Slater, Mette Jorgensen, Christine Dahl, Patricia O'Hare, Helen A Spoudeas, Hong-Wei Gan, Kristian Aquilina, Yen Ch'in Chang, Felice D'Arco, Darren Hargrave, Enrico Opocher
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: The treatment aim of childhood optic pathway glioma (OPG) is visual preservation. However, long-term outcomes and prognostic factors implicated remain largely unknown. METHODS: We undertook a retrospective study of infants and young children (IYC) ≤3 years with OPG and logMAR visual acuity (VA) at baseline/follow-up. We derived Overall- (OS), Progression-free (PFS), Radiotherapy-free (RTFS) and Visual event-free survival (vEFS) curves and analysed prognostic factors for visual deterioration and WHO defined blindness (&amp;gt;1.3 logMAR both eyes). RESULTS: Of 81 IYC-OPG (147 evaluable eyes) baseline vision was below 5%ile for age in 33 (41%) and 27 (33%) in one or both eyes respectively, within normal range in 21 (26%). After observation (11), chemotherapy (66) or RT (4), radiological progression occurred in 47 (58%), multiple times in 34.6% (range 2 - 8) and 10yr-PFS was 39.8%. Twenty had RT after 4.2 years from diagnosis (10yr-RTFS 72.4%) and 12% died (10yr-OS 89%). After 8.9 years VA was better/stable/ worse in 36%/32%/32% of subjects, with median time to visual event of 1.7 years (range 0.16 - 12) and 10yr-vEFS 41.3%. Final VA was reduced (&amp;gt;0.2 logMAR) in 23 (28.4%) and 43 (53.1%) in only one or both eyes respectively. Amongst those with unilateral impairment 13/23 affected eyes had no useful vision (light/no light perception). Amongst those with bilateral impairment best eye VA was &amp;gt; 1.0 log MAR in 22/43 (LP/NLP in 10). Infants &amp;lt; 1 year had significantly inferior 10-yrPFS (5.6%), post-chiasmatic involvement was associated with visual deterioration (HR 2.91, 95%CI=1.1- 7.7), and baseline bilateral abnormal for age vision predicted WHO blindness at follow-up (OR 17.9, 95%CI=3.2 – 101.1). CONCLUSIONS: Many IYC-OPG suffer multiple progressions with significant long-term visual morbidity. Predictive factors such as age, tumor location and baseline age-adjusted vision allow patients’ selection for early sight rehabilitation and consideration for experimental strategies preventing visual loss.
Shift of tumor-infiltrating immune cells after adding immune checkpoint inhibitors to neoadjuvant chemotherapy against NSCLC.
Authors: Yulin Ren, Zhenzhen Hui, Liuqing Zheng, QI Wang, Tao Wang, Shanshan Xiao, Hao Wang, Shaochuan Liu, Xiubao Ren
Journal: Journal of Clinical Oncology (2022)

e21002 Background: Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has revolutionized the treatment strategies in multiple cancer types, including NSCLC. Anti-PD1 combined with chemotherapy was superior to chemotherapy alone, but the fundamental mechanisms underlying their synergic effect remain incompletely understood. Here, we investigated the different effects induced by neoadjuvant pembrolizumab combined with chemotherapy (NAPC) and neoadjuvant chemotherapy (NAC) on tumor immune microenvironment in patients with NSCLC. Methods: We performed single-cell RNA-sequencing (scRNA-seq) to characterize the immune cells composition in seven patients with NSCLC received NAPC or NAC and validated these findings in a large population cohort (n = 58) utilized multiplex fluorescent immunohistochemistry (mIHC). Results: The results of scRNA-seq revealed that patients with NSCLC received NAPC or NAC displayed distinct immune cell composition, with myeloid cells being the predominant cells in NAC patients, whereas T cells, B cells and NK cells were more abundant in NAPC patients. Consistent with these results, mIHC confirmed that compared to NAC, NAPC was associated with increased infiltration of CD8 + T cells, CD8 + KLRG1 + effector cells, CD8 + CD127 + memory cells, CD4 + CD127 + memory cells, CD20 + B cells, accompanied by reduced CD66b + neutrophils but had no effect on other immune subsets examined, including CD68 + macrophage, CD68 + CD163 + M2 and mast cells. Survival analysis showed that, for both NAPC and NAC patients, CD8 + T cells, CD8 + KLRG1 + effector cells, CD8 + CD127 + memory cells were associated with favorable overall survival (OS), while CD66b + neutrophils was related to inferior OS. Moreover, CD20 + B cells appear to have a more pronounced effect than CD8 + T cells on the efficacy of NAPC, but not for NAC. Conclusions: Compared to neoadjuvant chemotherapy, the addition of pembrolizumab induced a shift in tumor-infiltrating immune cells toward enhanced antitumor immunity and reduced immunosuppressive cells. In additional, post-treatment tumor-infiltrating immune cells were able to provide prognostic value.
Primary analysis from the phase 2 study of continuous talazoparib (TALA) plus intermittent low-dose temozolomide (TMZ) in patients with relapsed or refractory extensive-stage small cell lung cancer (ES-SCLC).
Authors: Jonathan W. Goldman, Amy Lauren Cummings, Melody A. Mendenhall, Maria A Velez, Sunil Babu, Tirrell T. Johnson, Juan M. Alcantar, Shaker R. Dakhil, David E. Kanamori, William E. Lawler, Sidharth Anand, James Chauv, Edward B. Garon, Dennis J. Slamon
Journal: Journal of Clinical Oncology (2022)

8517 Background: TALA exhibits cytotoxic effects by inhibiting poly (ADP-ribose) polymerase (PARP) proteins 1 and 2 in addition to “trapping” PARP on DNA. TMZ has been shown to increase antitumor response when combined with TALA in SCLC models (Wainberg AACR 2016). TALA plus TMZ as second-line therapy for ES-SCLC may improve disease-related outcomes. Methods: This is a phase 2, open-label, single-arm study of the safety and efficacy of TALA plus TMZ in patients with ES-SCLC, relapsed or refractory to a first-line platinum-based regimen. Participants receive TALA 0.75 mg (or 0.5 mg if creatinine clearance &lt; 60 mL/min) po daily on 28-day cycles with TMZ 37.5 mg/m2 po on days 1-5. The primary endpoint is objective response rate (ORR) based on RECIST 1.1 criteria, versus a historical control of 15% ORR in second-line topotecan, with the null hypothesis rejected for 8 or more confirmed responses among 28 evaluable subjects (29% ORR). Secondary endpoints include progression-free survival, overall survival, duration of response, and time to response. Exploratory endpoints include biomarker studies such as status of DNA damage response genes (DDR) and patient reported outcomes. A Simon two-stage design was utilized to reach a total accrual of 28 evaluable patients. Results: Thirty-one subjects were enrolled, of which 3 were non-evaluable due to ineligibility (1) or early withdrawal of consent prior to first disease assessment (2). Eleven of 28 evaluable subjects (39.3%) achieved a confirmed partial response. The ORR was similar among platinum-refractory (3/6), -resistant (4/9), and -sensitive subgroups (4/13). The median time to response was 1.8 months (m), duration of response 5.8 m, progression free survival 4.5 m, and overall survival 11.9 m. Adverse events (AEs) were manageable, with grade ≥ 3 AEs being thrombocytopenia (61.3%), anemia (54.8%), neutropenia (41.9%), and atypical pneumonia (3.2%), which responded well to dose-hold or dose-reduction and transfusion or growth factor support as needed. Cell free DNA and tissue analysis demonstrated no germline DDR mutations among the trial subjects, but somatic DDR mutations at baseline and acquired during treatment were common. Three subjects remain on study treatment. Conclusions: The study exceeded its target response rate. This is the second trial to demonstrate a benefit of PARP inhibition with low-dose TMZ in SCLC (see Farago Cancer Discovery 2019). A phase 3 study is appropriate to confirm the benefit of this approach compared to currently approved options. Clinical trial information: NCT03672773.
Radiotherapy, volume reduction, and short-term surgical outcomes in the treatment of large myxoid liposarcomas.
Authors: Linus Lee, Sarah Tepper, Grant Owen, Dian Wang, Nicolas Lopez-Hisijos, Matthew W. Colman, Steven Gitelis, Alan T. Blank
Journal: Journal of Clinical Oncology (2022)

e23546 Background: While tumor volume reduction following radiation has been documented in myxoid liposarcomas, it is unclear whether large tumors experience similar volume reduction to smaller tumors. Methods: MRI studies performed before and after completion of pre-operative radiation therapy (RT) were examined. Tumor sizes were noted and categorized as large vs. small based on size &gt; 10 cm. Tumor volumes were calculated, and operative duration and major wound complications were recorded. Results: The median largest tumor dimension was 12.4 cm before RT and 8.7 cm after RT. The median tumor volume was 298.9 cm 3 before RT and 106.9 cm 3 after RT. There was no significant difference in the mean percent tumor volume reduction between large tumors and small tumors (p = 0.11, 56.3% vs. 64.5%). Operative duration most strongly correlated to post-RT MRI volume (R 2 = 0.674, p &lt; 0.001). Despite volume reduction, tumors that were large on presentation were more likely to experience major wound complications post-operatively. Conclusions: Radiation appears to be as effective at reducing myxoid liposarcoma tumor volume in large and small tumors. However, large tumors on presentation appear more likely to experience wound complications despite tumor volume reduction. Future studies should investigate disease-related outcomes as a factor of volume reduction in myxoid liposarcoma.[Table: see text]
Clinical characteristics and molecular features of non-small cell lung cancers (NSCLCs) following disease progression on immune checkpoint inhibitors (ICIs).
Authors: Justin F. Gainor, Arvind Ravi, Mark M. Awad, Mark Holton, Monica Arniella, Chip Stewart, Samuel Freeman, Ignaty Leshchiner, Andrew Chow, Brian S. Henick, Vamsidhar Velcheti, Aaron Timothy Griffin, Biagio Ricciuti, Jonathan W. Riess, Pasi A. Janne, Nir Hacohen, Jedd D. Wolchok, Matthew David Hellmann, Gad Getz
Journal: Journal of Clinical Oncology (2022)

e21178 Background: ICIs are cornerstones of therapy for advanced NSCLC. Despite dramatic and sometimes durable responses to therapy, most patients (pts) either (i) do not respond to therapy (intrinsic resistance), or (ii) subsequently progress after initial clinical benefit (acquired resistance). Currently, insights into the molecular mechanisms of resistance to ICIs in NSCLC are lacking. Methods: To investigate clinical and molecular features of pts progressing on ICIs, we identified pts who underwent repeat tumor biopsies on and/or after disease progression on ICIs and were included in the Stand Up 2 Cancer (SU2C)/Mark Foundation multi-institutional cohort. Biopsy specimens underwent whole-exome sequencing (WES) and/or whole transcriptome sequencing (RNAseq). Results: We identified 37 pts who underwent a total of 47 repeat biopsies on or after ICIs. Six pts underwent multiple post-ICI biopsies (range 2-4). Twenty-five pts (68%) received PD-(L)1 inhibitor monotherapy, 6 (16%) received PD-(L)1 plus CTLA-4 inhibitors, and 6 (16%) received other PD-1 inhibitor-based combinations. Overall, the objective response rate was 46% among pts undergoing repeat biopsies (complete response 2 [5%], partial response 15 [41%], stable disease 14 [38%], progressive disease 5 [14%] and not evaluable 1 [3%]). Median progression-free survival (PFS) was 8.1 months. In total, pre-ICI biopsy specimens were available in 20 pts. WES and RNAseq were performed on 67 and 44 specimens, respectively. Median tumor mutation burden (TMB) in pre-ICI specimens was 5.0 mutations/Mb versus 4.9 mutations/Mb in post-ICI specimens ( p= 0.3, Mann-Whitney U test). Among 20 paired pre/post-ICI specimens, there was no significant difference in TMB (pre-treatment median 3.9 mutations/Mb; post-treatment median 4.3 mutations/Mb; p= 0.7, Wilcoxon signed-rank test). One pt with a complete response acquired a nonsense mutation in B2M, and one pt with a partial response acquired a nonsense mutation in JAK1. Among 10 paired pre/post-ICI specimens that underwent RNAseq, we observed significant decreases in granzyme B and perforin in post-ICI specimens ( p= 4×10 -5 and p= 2×10 -3 , respectively, limma-voom analysis). Conclusions: Genomic alterations impairing antigen presentation (e.g., B2M) or immune activation (e.g., JAK1) may enable resistance to ICIs in a small subset of cases. However, the majority of repeat biopsies obtained from pts progressing on ICIs lacked clear genetic mediators of resistance, suggesting the presence of additional tumor-intrinsic and/or tumor-extrinsic factors underlying resistance to ICIs in NSCLC.
Forward-viewing echoendoscope plus gel immersion technique in a patient with Billroth II reconstruction
Authors: Tatsuya Ishii, Tsuyoshi Hayashi, Kuniyuki Takahashi, Toshifumi Kin, Akio Katanuma
Journal: Endoscopy (2022)

Endoscopic ultrasound (EUS) in patients with surgically altered anatomy is often difficult, and forward-view echoendoscopy (FV-EUS) has proven to be useful in such cases [1]. Recently, the gel immersion technique has been used for various endoscopic diagnostic and therapeutic procedures [2] [3] [4]. In the case reported here, the bile ducts and papilla were successfully observed in a patient with a Billroth II reconstruction using FV-EUS and the gel immersion technique ([Video 1]).
Strategies for implementation cancer care delivery studies in a community setting.
Authors: Courtney Chun, Christa M Braun-Inglis, Valerie Ferguson, Laura Peterson, Jeffrey L. Berenberg
Journal: Journal of Clinical Oncology (2022)

e13525 Background: Cancer care delivery Research (CCDR) is a multidisciplinary science that seeks to improve clinical outcomes and patient well-being by intervening on patient, clinician and organizational factors that influence care delivery. Many CCDR protocols also use implementation science to evaluate how best to introduce promising and previously established interventions into everyday care. These types of studies do not typically utilize research and clinic staff in the same ways as traditional treatment trials. One of the main goals of CCDR is for clinics to continue to use the intervention past the time of protocol participation. Even though these studies intend to improve cancer care delivery in the community, it is often difficult for community sites to embrace and prioritize CCDR due to their differences from typical treatment trials. Our recent observatory research highlights one Minority/Underserved (M/U) NCORPs key strategies for successful implementation of a decision aid CCDR trial in a community setting. Methods: HI M/U NCORP identified multiple steps prior to opening and enrolling patients onto a CCDR implementation trial at our community site. Step 1) Identifying an engaged physician and an advanced practice provider (APP) to be champions for the trial at the clinic. 2) Identifying and engaging key clinic staff and ensuring the workflow is feasible in the clinic. Key processes utilized during the entire course of the trial were also identified. 3) Research staff only coordinating and completing purely study related activities and not implementation activities. 4) Engaging other non-traditionally research involved administration staff and department management. 5) Utilizing ongoing clinic staff input to enhance trial success and optimize clinic workflow. Results: Using the strategies mentioned above, Hawai’i M/U NCORP was able to successfully open and enroll to an internet based CCDR implantation trial at a community clinic from 2019 through 2021. Not only were we able to achieve the highest accrual to a CCDR implementation trial to date within our NCORP, but also managed to do so at a clinic that had previously had minimal involvement in clinical trials in the past. Providers within the clinic received very positive reviews from their patients regarding the trial elements and the clinic has been working toward continuing the use of the material introduced by this CCDR implantation trial. Conclusions: Our successful use of these strategies described have not only been beneficial for our NCORP, but has made a large impact on improving the quality of clinic care at a busy community site. Our involved multi-step opening strategies set the stage for a seamless clinic workflow throughout the trial. This research has proven that these strategies can lead to the success of CCDR implementation studies in a community practice.
Assessing the quality of learning curve through a standardized proficiency score and the impact of learning curve on trifecta outcomes of robot-assisted radical prostatectomy (RALP): Results of a multicentric series
Authors: U. Anceschi, A. Galfano, P. Dell'Oglio, C.A. Bravi, L. Misuraca, G. Tuderti, M.C. Ferriero, S. Albisinni, L. Luciani, S. Secco, G. Petralia, E. Di Trapani, A. Brassetti, R. Mastroianni, A.M. Bove, M.C. Ferriero, T. Cai, M. Puglisi, D. Mattevi, T. Quackels, G. Malossini, A.M. Bocciardi, G. Simone
Journal: European Urology (2022)
Real-world treatment patterns in the U.S. and trends pre-post CARD trial among patients with metastatic castration-resistant prostate cancer.
Authors: Shashank Ghantoji, Channing Yu, Amrita Sawhney, Clare Byrne, Jackson Tang, Kyle Runeckles, Jeetvan Patel
Journal: Journal of Clinical Oncology (2022)

e17024 Background: Numerous treatments with different mechanisms of action are approved for metastatic castration-resistant prostate cancer (mCRPC). The sequencing for management of these patients has been evolving post availability of trials such as the CARD trial, looking at clinical outcomes post androgen receptor pathway inhibitor (ARPI) and docetaxel. This study examined real-world treatment patterns and sequencing among United States patients with mCRPC. Methods: This retrospective cohort study used Flatiron Health electronic health record data from Jan 1, 2013 to June 30, 2020 (study period). Included patients were male aged ≥18 years, had a confirmed diagnosis of mCRPC within the study period, and received ≥1 systemic therapy post-mCRPC diagnosis. Index date was the date of first-line (1L) therapy initiation post-mCRPC diagnosis. Patient characteristics and treatment patterns were evaluated descriptively. Across analyses, treatments were grouped as follows: ARPI (abiraterone, enzalutamide), taxane (docetaxel, cabazitaxel), sipuleucel-T, radium-223, targeted therapy (TT; olaparib, rucaparib), mitoxantrone, combo therapy (any combination regimen containing ≥1 of the preceding therapies), and other (any other therapy or combination of therapies). Results: 2,588 patients were included in the study; mean±SD age was 72±8 years and 66% were White. The most common 1L therapy was ARPI (63%), followed by taxane (11%), combo therapy (11%), radium-223 (6%), sipuleucel-T (6%), and other therapy (2%). No patient received TT or mitoxantrone alone in 1L. Median time to next treatment post-1L was longest for combo therapy (8.1 months) and ARPI (7.6 months) and shortest for sipuleucel-T (3.4 months). The most common sequence of treatment for mCRPC patients was 1L ARPI to another ARPI at second-line (2L) (29%); taxane and combo therapy (both 14%) were the next most common (Table). Treatment patterns were similar pre- and post- read-out of the CARD trial. Conclusions: The majority of mCRPC patients who receive 1L ARPI will receive another at 2L rather than switching to an alternative type of treatment.[Table: see text]